Anti-tumour agent

Figure 3.117 (a) JM-216, a platinum(IV) compound under clinical tests as an orally administered anti-tumour agent (b) the platinum(II) product of in vivo reduction, likely to be the active... 

Tiekrnk, E.R.T. (2003) Gold Compounds in Medicine Potential Anti-Tumour Agents. Gold Bulletin, 36, 117—124. 

In ribonuclease-S [PtClJ2- binds to the sulphur of methionine (63). In this case however greater interest centres on the use of cis-[PtenCl2] which is one of the best anti-tumour agents. The conditions of application of the reagent were sulphate media s pH 5.5. This is a more favourable attacking medium than that used in the experiments with lysozyme. We quote results from the original paper (63). 

The effect of platinum in a bacterial cell is to act in a very selective way — on cell division or causing lysis of lysogenic bacteria. It is likely that these changes are due to site specific attack on particular proteins or on particular bases in RNA or in DNA. It is necessary now to describe this attack in detail and to develop new probes for following the site in vivo. This exercise can be followed by a parallel examination of how cis- [Pt (NH3) 2CI2] acts as an anti-tumour agent. Here we only point to some interesting observations. 

There is evidence that both classes of anti-tumour agent act by inhibiting DNA synthesis as opposed to RNA or protein synthesis. Many agents which inhibit DNA synthesis cause lysis of lysogenic bacteria-X-rays, ultra-violet light, many carcinogens (3, 90). 

It must be emphasized that the enyne units are present in several anti-tumour agents and anti-biotics. 

MAb-based constructs represent, as described, a heterogeneous class of anti-tumour agents with remarkable efficacy in the treatment of experimental cancers in animals. Several MAb and immunoconjugates have been evaluated further in cancer patients, and the results have indicated that some have activity at safe doses. 

Figure 1.12. Some flavonoids, xanthines and terpenoids. Chrysoplenol B and axillarin are two flavonoids exhibiting anti-viral activity against Rhinovirus (causative agent of the common cold). Examples of xanthines include caffeine and theophylline. Terpenes are polymers of the 5-carbon compound isoprene. Perhaps the best-known such substance discovered in recent years is the diterpenoid taxol, which is used as an anti-tumour agent...

Anthraquinones. - Murugesan and colleagues have investigated the effects of substituents on the photochemical properties of these compounds, many of which are anti-tumour agents. Cynodontin and a methoxylated derivative were shown to generate both 02 and 02 upon irradiation in the 300-700 nm region. 

Kiimmerer, K., Steger-Hartmann, T. and Meyer, M. (1997) Biodegradability of the anti-tumour agent ifosfamide and its occurrence in hospital effluents and communal sewage. Water Res.,... 

Arthurs CL, Raftery J, Whitby HL, Whitehead RC, Wind NS, Stratford D (2007) Arene cis-Dihydrodiols Useful Precursors for the Preparation of Analogues of the Anti-Tumour Agent, 2-Crotonyloxymethyl-(4/ ,5/ ,6/ )-4,5,6-trihydroxycyclohex-2-enone (COTC). Bioorg Med Chem Lett 17 5974... 

For example, samples of animal tissue can be investigated without the need to isolate any specific substance. This has been used to study the bonding of platinum atoms in animal organs, following the administration of platinum complexes as anti-tumour agents. 

Follow-on functionalisation with molecular moieties of biological importance, such as anti-tumour agents (e.g. 5-fluorouracil) currently appears particularly attractive. In this context, acetylation is particularly suitable as functionalisation reaction for oligo/polyamine dendrimers. It renders the dendrimers more water soluble, which is essential for biomedical applications [25]. The toxicity of den-... 

The concept of postmodification of the molecule s periphery is thus not only appropriate for the introduction of simple functionalities determining the physical and chemical properties of the molecule (e.g. solubility), but also allows the introduction of complex function-bearing units (e.g. catalytically active units, anti-tumour agents), which could be too sensitive for convergent dendrimer synthesis. 

The N-oxide of indicine (49) exhibits anti-tumour activity in experimental tumour systems, without some of the toxic effects associated with other pyrrolizidine alkaloids. The N-oxides of echinatine and europine show similar anti-tumour activity against P 388 lymphocytic leukaemia tumours.23 Indicine N-oxide is metabolized to the free base in rabbits and humans,62 although the N-oxide is the more active anti-tumour agent. It has been suggested that the conversion of indicine N-oxide into indicine is not essential for its anti-tumour activity.63 Indicine N-oxide is the first pyrrolizidine alkaloid to be tested as an anti-tumour agent in humans. The toxicity and pharmacokinetics of this compound have been studied in 29 patients with advanced cancers.64 The major toxic effect was myelosuppression, but acute liver damage was not observed. 

Metabolites from cyanobacteria are generally of amino acid or polyketide origin and frequently show potent biological activity. The series of dolastatin metabolites, exemplified by dolastatin-10 (Structure 2.18), are linear peptides which show potent cytotoxic activity and are of clinical interest as anti-tumour agents. Originally isolated in very low yield from the Indian Ocean sea hare Dolabella auricularia, dolastatins are now known to be cyanobacterial products.43,44 The discovery of a microbial source for these pharmaceutically important compounds will facilitate study of their biosynthesis and could potentially lead to the production of structural analogues by provision of modified biosynthetic precursors to the cultivar. As discussed below and in Section VI, toxic secondary metabolites from cyanobacteria have often been implicated in the chemical defenses of sea hares.45"17... 

Kopf-Maier P (1994) Complexes of metals other than platinum as anti-tumour agents. Eur J CUn Pharmacol 47 1-16 Krause HW (1959) Nichtenzymatische oxydative Desaminierung des Alanins dutch Pyridoxalphosphat. Chemiische Ber 92 1914-1917... 

Thomas H, Balkwill F. Assessing new anti-tumour agents and strategies in oncogene transgenic mice. Cancer Metastasis Rev 1995 14 91-5. 

Cyclization via intramolecular olefination of complex phosphonates remains the most important method of synthesis for complex natural macrocycles. Examples include syntheses of 20-membered macrolide antibiotic, aglycones of venturicidins A and B,108 oleandomycin (a 14-membered macrolide antibiotic), 109 the 19-membered macrocyclic antibiotic, anti-tumour agent (-t-)-hitachimycin,ll0 and the macrocyclic lactones (183).1H Cyclization of the phosphonate (184) under Masamune-Roush conditions has been used to synthesize the 28-membered macrolactam myxovirescin B.112... 

Steroid hormone analogues [e.g. (471)] carrying the cyclophosphamide system have been synthesized as potential anti-tumour agents. ... 

Other Anti-Tumour Agents with Alkylating Properties.166... 

This correlation between chemical reactivity and anti-tumour action later enabled a rational approach in the design of anti-tumour agents. On the one hand, mustards were synthesised with half-lives of only seconds, for administration directly into arteries supplying the tumour and, on the other hand, agents were prepared with very long half-lives and therefore inactive but which might be selectively metabolised in the tumour to active compounds. 

Table 3. The effect of different classes of anti-tumour agent on some transplanted tumours. The TLX5 (R) is a line with acquired resistance to a triazene and is cross resistant to BCNU. Triazenes and BCNU are active against tumours which do not respond to anti-metabolites and others that are insensitive to alkylating agents. The platinum complex was cis dichloro-bis(cyclopentylamine)platinum(II) and the triazene 5-(3,3-dimethyl-l-triazeno)-4-carbethoxy-2-me thy limidazole...

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